Na⁺/H⁺exchanger isoform 1-induced osteopontin expression facilitates cardiac hypertrophy through p90 ribosomal S6 kinase

Abstract

Cardiovascular diseases are the leading cause of death worldwide. One in three cases of heart failure is due to dilated cardiomyopathy. The Na/H exchanger isoform 1 (NHE1), a multifunctional protein and the key pH regulator in the heart, has been demonstrated to be increased in this condition. We have previously demonstrated that elevated NHE1 activity induced cardiac hypertrophy in vivo. Furthermore, the overexpression of active NHE1 elicited modulation of gene expression in cardiomyocytes including an upregulation of myocardial osteopontin (OPN) expression. To determine the role of OPN in inducing NHE1-mediated cardiomyocyte hypertrophy, double transgenic mice expressing active NHE1 and OPN knockout were generated and assessed by echocardiography and the cardiac phenotype. Our studies showed that hearts expressing active NHE1 exhibited cardiac remodeling indicated by increased systolic and diastolic left ventricular internal diameter and increased ventricular volume. Moreover, these hearts demonstrated impaired function with decreased fractional shortening and ejection fraction. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) mRNA was upregulated, and there was an increase in heart cell cross-sectional area confirming the cardiac hypertrophic effect. Moreover, NHE1 transgenic mice also showed increased collagen deposition, upregulation of CD44 and phosphorylation of p90 ribosomal s6 kinase (RSK), effects that were regressed in OPN knockout mice. In conclusion, we developed an interesting comparative model of active NHE1 transgenic mouse lines which express a dilated hypertrophic phenotype expressing CD44 and phosphorylated RSK, effects which were regressed in absence of OPN.

Osteopontin: A Promising Therapeutic Target in Cardiac Fibrosis

“…Enhanced expression of OPN appears to play an important role in the remodeling of the heart post-MI, as well as in left ventricular hypertrophy [36][37][38][39]. One putative route through which the OPN could be mediating its hypertrophic effects is through the activation of pro-hypertrophic kinases and pathways.…”

“…This was emphasized in a study in which the activation of NFATc1 and GATA-3 (both pro-hypertrophic factors) were significantly reduced in OPN-deficient mice [41]. OPN has also recently been shown to mediate the hypertrophic response induced by cardiomyocyte expression of the activated form of Na + /H + exchanger isoform 1 (NHE1) [13,39,40,42]. Transgenic mice expressing active, cardiac-specific NHE1 showed alterations in gene expression that led to both CH and an upregulation of OPN as well as its related molecules, including fibronectin, CD44, integrin receptors, MMPs, and signaling kinases [42].…”

“…Interestingly, transfection of cardiomyocytes with siRNA-OPN significantly abolished the NHE1-induced hypertrophic response, as well as significantly reducing the activity of NHE1 in cardiomyocytes expressing active NHE1 [13]. Moreover, in the double transgenic mice expressing active NHE1 in which OPN was knocked out, cardiac hypertrophic parameters, including increased collagen deposition, upregulation of CD44, and phosphorylation of p90 ribosomal s6 kinase (RSK), were significantly reduced when compared to NHE1 transgenic mice [39]. In another model where CH was induced by transverse aortic constriction (TAC) in serum-and glucocorticoid-inducible kinase (SGK1) SGK1 +/+ mice, a marked increase in both OPN and NHE1 expression/activity was shown [43].…”

“…Many studies have demonstrated the efficacy of partial or complete OPN inhibition in a variety of preclinical models of diseases, including CH [15,37,39], coronary artery disease [24,28,58,59], DCM [46], diabetic cardiomyopathy [48], heart failure [52], and cardiac fibrosis [13,15,38,39,60]. The earliest study by Matsui et al demonstrated that the Ang-II-induced elevation in blood pressure, collagen deposition, and development of cardiac fibrosis was significantly reduced in OPN −/− mice compared to wild type (WT) mice [38].…”

“…In another study where the genetic model of heart failure was examined (double desmin −/− OPN −/− mice), the deficiency in OPN reduced fibrosis and improved the systolic properties of desmin −/− myocardium [52]. Interestingly, in the NHE1-induced CH model of mice, knocking out OPN was sufficient to significantly reduce collagen deposition, upregulation of CD44, and phosphorylation of RSK, features that are characteristic of cardiac fibrosis [39]. Taken together, these findings suggest that benefits from knocking out OPN could be possible in specific settings of cardiac dysfunction, including diabetes, CH, and heart failure.…”